A new class of cholesterol-lowering agents known as PCSK9 inhibitors (PCSK9Is) are back in the headlines for two seemingly contradictory reasons: the release of new clinical trial results showing that treatment with alirocumab (Praluent®), one of two PCSK9Is currently on the market, is indeed associated with favorable cardiovascular outcomes; and an announcement of unprecedented price reductions for the same drug as part of a new deal between the manufacturer and a large pharmacy benefit manager. Since when does more positive clinical evidence for a drug lead to lower prices?

PCSK9Is offer a fascinating case study in the intersections between pharmaceutical innovation, specialty drug pricing, real world budget concerns, and patient access. This is not the first time PCSK9Is have been the focus of media attention. They reignited national debate about the high cost of medications and the need to rein in prescription drug spending in the wake of their approval by the Food and Drug Administration (FDA) in the summer of 2015. Their efficacy in lowering stubbornly high LDL cholesterol was impressive; however, payers were concerned with their list price (approximately $14,000), as well as the absence of data at launch showing that the cholesterol reductions were accompanied by lower rates of cardiovascular events such as heart attacks and strokes.

In addition, a report issued in late 2015 from the Institute for Clinical and Economic Review (ICER) suggested PCSK9Is offered low value at their proposed list prices. With an unusually large population of eligible patients (approximately 9 to 11 million), payers were faced with the daunting challenge of ensuring access to an innovative therapy while guarding against its “budget busting” potential. The subsequent stakeholder responses offer key insights into effective – and not so effective – methods to balance and harmonize these concerns.

Fearing What’s Past Is Prologue
The PCSK9I coverage dilemma came on the heels of another major development in the specialty drug market. In the prior year, hepatitis C drugs such as sofosbuvir (Sovaldi®) had garnered widespread attention. These therapies were heralded as “miracle cures” for patients with hepatitis C but largely caught payers off guard.

While high-priced orphan drugs for narrow patient populations had been around for some time, both public and private payers were unprepared for the financial strain that accompanied high-cost specialty drugs for such a large group of patients. As payers began scrutinizing the drug pipeline for other potentially costly therapies that could see widespread uptake, PCSK9Is loomed large on the horizon (with annualized spending projections ranging from $21.4 -$113 billion depending on uptake assumptions). The “post-Sovaldi” environment made payers understandably reluctant to cover high-cost drugs that had large target populations but lacked solid outcomes data. And although PCSK9Is were considerably less expensive than the short-term hepatitis C therapies, they were aimed at a patient population that would likely require lifelong treatment.

A Measured Introduction
Rather than deny coverage outright, most payers opted to place the drugs on their formularies while implementing prior authorization (PA) policies. PA is a commonly used tool that requires the physician to submit special forms and/or clinical information to the insurance plan in advance of prescribing a medication, to obtain pre-approval for coverage. PA policies are used by payers as a sort of “filter” to ensure access for patients with a clear clinical need while limiting uptake among patients who could be treated with less expensive conventional therapies. The ideal goal of PA policies is to limit overprescribing or inappropriate use of a medication, thereby providing both clinical safeguards and ensuring judicious use of healthcare dollars.

In some respects, PCSK9Is are exactly the sort of expensive therapy where appropriately designed PA requirements could be useful. When they were first approved, approximately 5 percent of the estimated target population for PCSK9Is were patients with familial hypercholesterolemia (FH)—a genetic disorder that causes elevated cholesterol from birth, significantly increasing the risk for early, aggressive cardiovascular disease. However, the remaining 95 percent fell under a second approval category: those with uncontrolled atherosclerotic cardiovascular disease (ASCVD). In this latter group, clinical need for PCSK9Is is less straightforward. Unsatisfactory response to traditional statin treatments in ASCVD is sometimes due to modifiable factors such as suboptimal dosing, medication non-adherence, and patient lifestyle. In theory, requiring physicians to demonstrate clinical need for ASCVD patients might be a reasonable way to reduce any risk of overprescribing PCSK9Is.

But before long, there were reports that PA requirements for PCSK9Is were resulting in highly restricted access to treatment. In one study, approximately 80 percent of PCSK9I prescriptions were rejected by the insurer on the first attempt, with less than half of patients ultimately receiving approval after further attempts. Another study examined PCSK9I prescription rejection rates by indication, and the findings were striking: 57.5 percent of patients with ASCVD were denied coverage, but so were 63.3 percent of those with FH. Greater than 40 percent of the prescriptions took more than 2 months for approval by the insurer. These studies were unable to examine the clinical validity of these rejections and delays, but they raised concerns that PA was functioning as a blockade rather than a gate.

Behind The Curtain
Our recent research offered a rare glimpse into PA policies across U.S. public and private payers and provided support for these concerns. In our analysis, PCSK9i PA forms were found to contain 3 to 11 times the number of PA criteria or fields required for comparator cardiometabolic drugs that would have likely been prescribed by the same types of providers. Policies also more frequently required submission of patient medical records as supporting documentation for responses on the PA forms (rather than the traditional physician attestation). Some of the requested documentation (such as off-treatment cholesterol levels) would likely prove difficult for prescribers to obtain, particularly if patients had changed providers over time.

Most striking? Patients with FH – that small subgroup for whom even optimal standard (statin) therapy is often not sufficient and among whom up to 58 percent of women and 85 percent of men will have a heart attack by age 60 – were subject to just as many administrative hurdles as those with ASCVD. In fact, payers frequently required results of genetic testing for FH, even though this is not standard clinical practice in the U.S. and is rarely covered by insurance.

Im-precision Medicine
Perhaps due in part to these uniquely burdensome PA requirements, adoption of PCSK9Is was indeed sharply lower than expected, with actual spending on these drugs in the U.S. less than 3 percent of analyst predictions in the first year. There was no budget catastrophe as initially feared. Yet rather than limiting use to only those patients with the greatest need, one-size-fits-all PA policies may have inadvertently created an environment that rewarded administrative competence rather than clinical necessity.

In light of the time and attention to detail required to navigate a complex PA process successfully, this meant that an FH patient being treated at an understaffed rural clinic might be denied therapy that a patient with less clear need—but a well-resourced provider—might receive. In addition to creating the potential for health disparities, such an approach makes little economic sense from a payer perspective, since it does not focus spending on the group of high-risk patients in whom the treatments would offer the most value. With such high risk of major cardiac events in FH patients and certain ASCVD patients, the downstream costs of intensive healthcare utilization and poor outcomes associated with excessive barriers to appropriate prescribing are likely to be substantial.

Payers And Manufacturers Are Charting A New Course
Over the past year, some payers have opted to revise their policies in light of calls from advocacy groups, new cardiovascular outcomes trial data, and clinical guidelines. For instance, in March 2017, Express Scripts partnered with the FH Foundation, a leading research and patient advocacy group, to revise the diagnostic criteria used for FH and offer alternative pathways for approval, with modifications for ASCVD patients as well. In June 2017, CVS Health also announced a dramatic shift in how it was approaching PA for PCSK9Is. CVS will now treat PCSK9Is the same as most other drugs on the formulary and accept physician’s attestation as sufficient evidence for the need for these medications, rather than requiring medical record documentation.

While the deal with Express Scripts will take effect in July 2018, Sanofi/Regeneron have indicated they are seeking similar arrangements with a number of payers to ensure expanded access for alirocumab. Amgen has also indicated that it is negotiating pricing agreements with multiple payers in an effort to expand patient access to evolocumab. While these arrangements are still in their infancy, they could mark the start of a wider trend across the specialty drug market.

What Insights Can We Glean From The PCSK9I Story?
The lessons learned from PCSK9Is can inform the design of more effective approaches to balancing budget affordability and appropriate access for future beneficial but expensive specialty drugs for broad populations. First, we have learned that blunt one-size-fits-all and highly burdensome PA requirements and processes that reward administrative competence instead of fast-tracking clinical urgency are likely to stand in the way of value-based care and allow high-risk patients to fall through the cracks.

Second, we have learned that payers and manufacturers can work together and meet halfway in an attempt to improve access through innovative payment arrangements. While the effects of these new arrangements will take time to unfold, and the results will likely influence which strategies are favored in the future, such agreements in general may be a productive approach to balancing access and affordability. Financial barriers to access may also be alleviated as payers test out the strategy of passing on rebates to patients at the pharmacy counter in the form of lower out-of-pocket costs. If exclusive formulary access for one specialty drug agent in the class becomes a common feature of these new agreements, however, the impact of this reduction in patient and provider choice will need to be evaluated in future research, especially in classes where agents have different efficacy or safety profiles or other important differences. In the meantime, payers must ensure a reasonable process for approving formulary exceptions for patients with clinical need for off-formulary agents.

Third, the recent agreements to expand PCSK9I access occurred two-to-three years after the drugs entered the market. Stakeholders should seek to iron out the details of innovative payment agreements closer to a drug’s launch to avoid long delays in patient access.

Ultimately, if patients are truly to benefit from innovative therapies, all stakeholders -- including manufacturers, payers, and providers -- must engage in efforts to ensure appropriate drug pricing, utilization management, and prescribing.